Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease

Q: What are the key findings of this study?

The presence of both severe hypercholesterolemia (LDL-C ≥190 mg/dL) and an FH mutation was associated with a 4.3-fold increased risk of incident coronary heart disease compared to individuals with LDL-C <190 mg/dL and no FH mutation.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Without existing coronary heart disease (n=21426). Intervention: Severe hypercholesterolemia (LDL-C ≥190 mg/dL) and/or Familial Hypercholesterolemia (FH) genotype vs. Individuals with LDL-C <190 mg/dL and no FH mutation. Primary outcome: Incident CHD events (HR 4.3, 95% CI 2.3-7.8).

Q: What does this research mean for the field?

Severe hypercholesterolemia and familial hypercholesterolemia genotype are associated with an increased risk of premature coronary heart disease. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Yiyi Zhang; Jacqueline S. Dron; Brandon K. Bellows; Amit V. Khera; Junxiu Liu; Pallavi Balte; Elizabeth C. Oelsner; Sami S. Amr; Matthew S. Lebo; Anna Nagy; Gina M. Peloso; Pradeep Natarajan; Jerome I. Rotter; Cristen J. Willer; Eric Boerwinkle; Christie M. Ballantyne; Pamela L. Lutsey; Myriam Fornage; Donald M. Lloyd‐Jones; Lifang Hou; Bruce M. Psaty; Joshua C. Bis; James S. Floyd; Ramachandran S. Vasan; Nancy L. Heard‐Costa; April P. Carson; Michael E. Hall; Stephen S. Rich; Xiuqing Guo; Dhruv S. Kazi; Sarah D. de Ferranti; Andrew E. Moran

doi:10.1161/circulationaha.123.064168

Key result

Severe hypercholesterolemia with an FH mutation is linked to a ~4-fold higher incident CHD risk.

HR 4.3
95% CI 2.3-7.8
n=21,426

Why the study?

Does severe hypercholesterolemia and/or FH genotype increase the risk of incident CHD events in individuals without baseline CHD?

Key Points

To quantify the risk of incident coronary heart disease events associated with severe hypercholesterolemia (LDL-C ≥190 mg/dL) with or without a familial hypercholesterolemia genotype.
Analyzed 21,426 participants without preexisting coronary heart disease across 6 prospective cohort studies who underwent whole-genome sequencing.
Sequenced 3 familial hypercholesterolemia genes (LDLR, APOB, PCSK9) and classified variant pathogenicity using American College of Medical Genetics and Genomics criteria.
Estimated associations with incident coronary heart disease using multivariable-adjusted Cox proportional hazards models over a median follow-up of 20 years.
Across 21,426 participants, 1,334 (6.2%) had detreated LDL-C ≥190 mg/dL, 63 (0.3%) carried an FH mutation, and 30 (0.1%) had both.
During a median follow-up of 20 years with 3,091 incident events, compared to those with LDL-C <190 mg/dL and no mutation, adjusted HRs for incident CHD were 1.4 (95% CI, 1.2–1.6) for LDL-C ≥190 mg/dL alone, 2.8 (95% CI, 1.3–5.9) for FH mutation alone, and 4.3 (95% CI, 2.3–7.8) for both.
Mean detreated LDL-C levels were 197.0 mg/dL among mutation carriers versus 128.5 mg/dL among noncarriers.

Study Design

Type

Cohort (n=21,426)

Multicenter

Yes

Structured PICO

Does severe hypercholesterolemia and/or FH genotype increase the risk of incident CHD events in individuals without baseline CHD?

P

Population

21,426 adults without baseline coronary heart disease who underwent whole-genome sequencing, followed for a median of 20 years.

E

Exposure

Severe hypercholesterolemia (detreated LDL-C ≥190 mg/dL) and/or Familial Hypercholesterolemia (FH) genotype (mutations in LDLR, APOB, or PCSK9)

C

Comparator

Individuals with LDL-C <190 mg/dL and no FH mutation

O

Outcome

Incident CHD eventshard clinical

Main Result

Hazard Ratio: 4.3 (95% CI 2.3–7.8)

The presence of a familial hypercholesterolemia mutation is associated with a significantly higher risk of incident coronary heart disease, even when LDL-C levels are only modestly elevated.

Limitations

Exclusion of participants with preexisting CHD at baseline may underestimate the true population prevalence of genetically confirmed FH.
Estimation of detreated LDL-C values by applying a standard 30% increase does not account for different medication classes, doses, or heterogeneity in adherence and drug dose-response.
Detailed lipid-lowering medication information was not available in many participants, requiring estimation of detreated LDL-C values by applying a standard 30% increase, which does not account for different medication classes, doses, or heterogeneity in adherence.

Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

DLDonald Lloyd-JonesChair of Preventive Medicine, Northwestern University

“Yes, high cholesterol is worse for you than low cholesterol, but high cholesterol that's related to one of these single-gene disorders is particularly risky and even riskier than the polygenic variety.”

News Coverage

Implication

May support FH genotyping to refine CHD risk assessment beyond LDL-C; leaves open whether genotype-guided therapy improves outcomes.

Abstract

amilial hypercholesterolemia (FH) is a genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) from birth that often causes premature coronary heart disease (CHD). 1 FH can be diagnosed with established clinical criteria such as the Dutch Lipid Clinic Network criteria with or without genetic testing. 1 This study aimed to quantify the risks for incident CHD events associated with severe hypercholesterolemia (LDL-C ≥190 mg/dL) with or without an FH genotype.This analysis used data from 6 population-based prospective cohort studies: (1) Atherosclerosis Risk in Communities Study, (2) Cardiovascular Risk Development in Young Adults Study, (3) Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Jackson Heart Study, and (6) Multi-Ethnic Study of Atherosclerosis Study.All study protocols were approved by the Institutional Review boards at participating institutions, and all participants provided written informed consent.The analysis was restricted to 21 426 participants without existing CHD at baseline who underwent whole-genome sequencing.Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers trained in human subject con-fidentiality protocols may be sent to the coordinating center of each study cohort.Demographic characteristics, LDL-C, and other cardiovascular risk factors were measured with standardized protocols in each study.For individuals reporting use of lipid-lowering therapy at the time of LDL-C measurements, detreated LDL-C values were estimated by applying a 30% increase in LDL-C. 2 We analyzed gene sequences of 3 FH genes (low-density lipoprotein receptor [LDLR], apolipoprotein B [APOB], and proprotein convertase subtilisin/kexin type 9 [PCSK9]).3 Variant annotations based on the American College of Medical Genetics and Genomics criteria and reports from the ClinGen and ClinVar expert panels were used to determine the pathogenicity of a variant.Cox proportional hazards models were used to estimate the associations of LDL-C and FH genotype with incident CHD events.Age was used as the time scale, and models were stratified by study cohort and adjusted for race and ethnicity, sex, smoking status, body mass index, high-density lipoprotein cholesterol, systolic blood pressure, diabetes, use of lipid-lowering medications, and use of antihypertensive medications.

Discussion

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Cite This Study

Zhang et al. (2023) conducted a cohort in Without existing coronary heart disease (n=21,426). Severe hypercholesterolemia (LDL-C ≥190 mg/dL) and/or Familial Hypercholesterolemia (FH) genotype vs. Individuals with LDL-C <190 mg/dL and no FH mutation was evaluated on Incident CHD events (HR 4.3, 95% CI 2.3-7.8). The presence of both severe hypercholesterolemia (LDL-C ≥190 mg/dL) and an FH mutation was associated with a 4.3-fold increased risk of incident coronary heart disease compared to individuals with LDL-C <190 mg/dL and no FH mutation.

synapsesocial.com/papers/6a9ae1626d42ebad6da7479f https://doi.org/10.1161/circulationaha.123.064168

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Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease

Key Points

Study Design

Structured PICO

Main Result

Limitations

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease

Key Points

Study Design

Structured PICO

Main Result

Limitations

Key expert perspectives

Implication

Abstract

Discussion

Cite This Study

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